Abstract
The duration of the eclipse phase, from cell infection to the production and release of the first virion progeny, immediately followed by the virus-production phase, from the first to the last virion progeny, are important steps in a viral infection, by setting the pace of infection progression and modulating the response to antiviral therapy. Using a mathematical model (MM) and data for the infection of HSC-F cells with SHIV in vitro, we reconfirm our earlier finding that the eclipse phase duration follows a fat-tailed distribution, lasting 19 h (18–20 h). Most importantly, for the first time, we show that the virus-producing phase duration, which lasts 11 h (9.8–12 h), follows a normal-like distribution, and not an exponential distribution as is typically assumed. We explore the significance of this finding and its impact on analysis of plasma viral load decays in HIV patients under antiviral therapy. We find that incorrect assumptions about the eclipse and virus-producing phase distributions can lead to an overestimation of antiviral efficacy. Additionally, our predictions for the rate of plasma HIV decay under integrase inhibitor therapy offer an opportunity to confirm whether HIV production duration in vivo also follows a normal distribution, as demonstrated here for SHIV infections in vitro.
Highlights
Are short relative to the duration of the entire eclipse phase
Our goal is to determine the shape of the distributions describing the amount of time simian-human immunodeficiency virus (SHIV)-infected cells spend in the eclipse phase, i.e. from successful virus entry to the release of the first virion, and in the virus-producing phase, i.e. the duration of SHIV production from the release of the first to the last virion progeny by an infected cell
We have made use of a mathematical model (MM) combined with a Markov chain Monte Carlo approach to determine the shape of the distribution describing the time spent by SHIV-infected HSC-F cells in the eclipse and virus-producing phases
Summary
Are short relative to the duration of the entire eclipse phase. Under these conditions, the eclipse phase, which corresponds to the total duration of all these processes, will follow a normal distribution, as per the central limit theorem. It allows for some cells to take a much longer than average time to produce their first virion progeny, referred to as a fat-tailed distribution We believe this is because one of the processes involved in early SHIV replication is significantly longer than others, and possibly accounts for most of the eclipse phase’s duration. We have shown that a virus like influenza A which replicates its segmented, negative-strand vRNA using its own polymerase, i.e. following a process devoid of this particular bottleneck, has an eclipse phase duration that follows a normal distribution2–4 While we reconfirm this results for the eclipse phase distribution our main focus in the present work is on determining, for the first time, the shape parameter which describes the phase immediately following the eclipse phase, namely the virus-producing phase, i.e., the duration for which cells infected with SHIV will produce and release virion progeny before this process is shut down, possibly as cells undergo apoptosis. We evaluate the impact of assuming an exponentially vs a normally distributed virus-producing phase on the analysis of viral load decays observed in HIV patients treated with various antiviral regimens
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